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Inherited ichthyoses, defined as the generalized form of Mendelian disorders of cornification, are characterized by visible scaling and/or hyperkeratosis of most or all of the skin. This etiologically and phenotypically heterogenous group of conditions is caused by mutations in various different genes important for keratinocyte differentiation and epidermal barrier function. Diagnosing a specific entity is a particular challenge for the nonspecialist presented with the common clinical scaling. For the clinician, this review outlines an algorithmic approach for utilizing diagnostic clues to narrow down the differential diagnosis and to guide further testing and treatment options.

Ichthyoses constitute a large group of cornification disorders that affect the entire integument. The skin is characterized by visible scaling and in many cases by inflammation, for example, in bullous/keratinopathic ichthyosis or Netherton syndrome. From the viewpoint of classification it is useful to distinguish nonsyndromic from syndromic types of ichthyosis. Ichthyosis vulgaris and recessive X-linked ichthyosis are common disorders—often of delayed onset, in contrast to congenital ichthyoses, which belong to the group of rare diseases and present at birth with either the features of collodion membrane or congenital ichthyosiform erythroderma. The diagnostic steps are based on clinical data, analyses such as the steroid sulfatase activity test, skin biopsies, and genetic results. However, the dramatic increase in knowledge about the pathophysiology of these conditions has not led to a curative therapy so far. The therapeutic management is multidisciplinary and involves ichthyosis patient organizations in many countries. The mainstay of treatment remains with moisturizing creams containing, for example, urea, lactic acid and other humectants and keratolytics, regular bathing, and mechanical scale removal. Patients with lamellar ichthyosis or ichthyosiform erythroderma in particular profit from oral therapy with retinoids or retinoic acid metabolism-blocking agents.

Background Pre-Descemet corneal dystrophy (PDCD) is characterized by the presence of numerous, tiny, polymorphic opacities immediately anterior to Descemet membrane, which is a rare form of corneal stromal dystrophy and hard to be diagnosed. In vivo confocal microscopy (IVCM) is a useful tool to examine the minimal lesions of the cornea at the cellular level. In this article, we report a rare case of PDCD associated with X-linked ichthyosis and evaluate IVCM findings. Case presentation We present a 34-year-old male Chinese patient with PDCD associated with X-linked ichthyosis. Slit-lamp biomicroscopy showed the presence of tiny and pleomorphic opacities in the posterior stroma immediately anterior to Descemet membrane bilaterally. IVCM revealed regular distributed hyperreflective particles inside the enlarged and activated keratocytes in the posterior stroma. Hyperreflective particles were also observed dispersedly outside the keratocytes in the anterior stroma. Dermatological examination revealed that the skin over the patient’s entire body was dry and coarse, with thickening and scaling of the skin in the extensor side of the extremities. PCR results demonstrated that all ten exons and part flanking sequences of STS gene failed to produce any amplicons in the patient. Conclusions IVCM is useful for analyzing the living corneal structural changes in rare corneal dystrophies. We first reported the IVCM characteristics of PDCD associated with X-linked ichthyosis, which was caused by a deletion of the steroid sulfatase (STS) gene, confirmed by gene analysis.

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders.

Autosomal recessive congenital ichthyoses (ARCI) are rare genodermatosis disorders characterized by phenotypic and genetic heterogeneity. At least fourteen genes so far have been related to ARCI; however, despite genetic heterogeneity, phenotypes associated with mutation of different ARCI genes may overlap, thereby making difficult their clinical and molecular classification. In addition, molecular tests for diagnosis of such an extremely rare heterogeneous inherited disease are not easily available in clinical settings. In the attempt of identifying the genetic cause of the disease in four Italian patients with ARCI, we performed next-generation sequencing (NGS) analysis targeting 4811 genes that have been previously linked to human genetic diseases; we focused our analysis on the 13 known ARCI genes comprised in the panel. Nine different variants including three novel small nucleotide changes and two novel large deletions have been identified and validated in the ABCA12, ALOX12B, CYP4F22, and SULT2B1 genes. Notably, two patients had variants in more than one gene. The identification and validation of new pathogenic ABCA12, ALOX12B, CYP4F22, and SULT2B1 variants through multi-gene NGS in four cases of ARCI further highlight the importance of these genes in proper skin function and development.

Inherited ichthyosis is a monogenetic disease characterized by hyperkeratosis and scaling of the skin, with large interindividual variation in severity. It can affect quality of life for patients and their families. Population-based data on inherited ichthyosis are lacking, which hampers studies into its epidemiology. Based on medical record review, we validated diagnoses of inherited ichthyosis in two nationwide population-based registries commonly used for epidemiological research: The Danish National Patient Registry and the Danish Pathology Registry. The study period was January 1, 1977, through December 31, 2015. Validation samples were taken from one regional hospital without a specialized dermatological department and two specialized dermatological departments. Positive predictive values (PPVs) were estimated overall and for each coding system (ICD-8, ICD-10 and SNOMED), including for specific ICD-10 codes. We identified 1772 first-time diagnoses of inherited ichthyosis; 363 patients were diagnosed at the departments selected for validation, and 307 of these patients (84.6%) had medical records enabling validation. We observed an overall PPV of 73.3% (95% CI: 68.1-77.9). For ICD-8, ICD-10, and SNOMED diagnoses, the PPVs were 73.2% (95% CI: 58.1-84.3), 74.7% (95% CI: 69.0-79.7), and 46.2% (95% CI: 22.1-71.7), respectively. In analyses for ICD-10 diagnoses, we observed much higher validity of diagnoses from the specialized departments (PPV 79.7%; 95% CI: 74.1-84.3) than the regional hospital (PPV 5.9%; 95% CI: 0.6-24.3). The PPVs for specific diagnoses were 80.1% for ichthyosis vulgaris and 96.6% for X-linked ichthyosis but below 45% for remaining, rarer, subtypes. The PPV of first-time diagnosis of inherited ichthyosis made at specialized dermatological departments in the Danish National Patient Registry is approximately 80%. Diagnoses from the Danish Pathology Registry had low PPVs precluding their use for research.